CHAPTER Genetics of glaucoma

Introduction

That primary open-angle glaucoma (POAG) and, especially, glaucoma occurring in childhood or associated with other developmental anomalies had familial characteristics has been known since the mid nineteenth century. Von Graefe described multiple families in which glaucoma had appeared in several generations.1 Family members of patients with POAG are more likely to have the disease than family members of those without glaucoma in the general population.2 A positive family history of glaucoma (especially a first-degree relative) is indeed a risk factor for POAG.3 Concordance of glaucoma is higher between monozygotic twins than dizygotic twins as would be expected if the disease was at least partially inherited.4

Elevated intraocular pressure (IOP), reduced facility of outflow, increased pressure response to corticosteroids and cup-to-disc ratio all have hereditary tendencies.5–10 The Beaver Dam Eye Study demonstrated that elevated IOP has both polygenetic and environmental influences.11 That same study showed an even greater heritability of optic nerve parameters associated with POAG such as vertical cup-to-disc ratio than even IOP.12 Similar findings were reported by the Salisbury Eye Study with the heritability of IOP estimated at 0.29 and that of cup-to-disc ratio at 0.56.13 A recent analysis of the Blue Mountains Eye Study data from Australia showed that genetically influenced IOP variance accounted for about 18% of the glaucoma in that large population study.14 The studies of both Becker and Armaly found that the development of elevated IOP following 6 weeks of topical corticosteroid treatment did roughly fit an autosomal recessive type of inheritance pattern. However, the pattern of inheritance of the actual disease did not seem to fit any of the classical Mendelian forms of inheritance such as autosomal recessive or sex-linked recessive.7–10

In a different condition, small eyes tend to run in families and angle-closure glaucoma is associated with small eyes. Certain developmental anomalies of the eye that are associated with glaucoma have been known for many decades to be familial in nature. Clearly, genetics plays an important role in many different forms of glaucoma.We still have a long way to go to sort out the effects of genetics versus environment but the serious study of these factors has begun. Science has given us tools that will continually accelerate this knowledge base.

The recent completion of the human genome project has offered a fascinating and hopeful glimpse into the future of medicine. Conceivably, in the not-too-distant future, we will have reclassified the glaucomas into more genetically appropriate conditions, we will be able to identify conditions like congenital glaucoma in utero as

well as identify those patients at high risk for openand closed-angle glaucoma while still in childhood or young adulthood so appropriate monitoring can be accomplished. Identifying the genes associated with various kinds of glaucoma also raises the possibility that we may be able to attach reparative genes to non-pathologic viruses or other vectors and actually prevent these diseases from occurring at all. An example of this kind of possibility has been reported with retinoblastoma; in a family where the father had bilateral retinoblastoma, as did the first born child (as well as pinealoma), the development of retinoblastoma in subsequent children was prevented by a technique called pre-implantation genetic diagnosis in which a single fertilized egg lacking the retinoblastoma gene was chosen for implantion in the uterus from several in-vitro inseminated oocytes. The resulting child did not have retinoblastoma (or any other tumor) with 6 months follow-up.15 Pharmacogenetics may also allow us to tailor our therapy of those diseases that slip through the genetic screens as well of those that are not genetically reparable to enable each patient to have the most effective and efficient therapy (Box 20-1).

As far as glaucoma is concerned, none of the promises have yet been realized; we have only just begun to travel down this road. What we have learned so far seems on the surface to be dull and includes an ever increasing list of glaucoma conditions associated with specific gene defects. Despite having found more than a dozen genes associated with one or another form of glaucoma, collectively these discoveries can explain less than 10% of the total cases of glaucoma.This chapter will try to outline what we have achieved so far. Because of improvements in methodology, the knowledge is coming at a faster and faster pace.While the subject matter may be only facts right now, what lies around the corner is exciting.Already, the ability to develop animal models of glaucoma using specific genetic defects (knockout rodents, etc.) has improved our understanding of some

Box 20-1  Potential benefits for glaucoma patients of genetic studies

Better understanding of the pathogenesis of the glaucomas.

Newer and better classification based on cellular/molecular mechanisms. Potential for genetic repair of mutations pre-implantation, in utero or early

in life before glaucoma damage occurs.

Identification of potential or actual victims in utero or early in life so appropriate repair, monitoring and/or therapy can be initiated before visual loss.

Development of therapy targeted specifically at the molecular or cellular defect.

Using pharmacogenetics to develop and target individual therapy having the most efficacy and efficiency as well as least side effects.